The present invention relates to a synthetic method of preparing amlodipine in a high yield.
Amlodipine, a generic name for the compound of formula (I), 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(2-chlorophenyl)-6-methyl- 1,4-dihydro-3,5,-pyridine dicarboxylate, is a long-term calcium-channel blocker useful for treating cadiovacular diseases such as stenocardia, hypertension and congestive cardioplegic. This compound is asymmetric due to the presence, around the rotationally restricted biaryl axis, of two different ester residues: 
There have been reported a number of methods for amlodipine synthesis but these methods generally suffer from the problem of low productivity caused by low yields observed at the critical Hantzsch reaction step, as further explained below.
For example, Korean Patent Publication No. 87-909 discloses a method for preparing amlodipine represented by Scheme 1: a 1,4-dihydropyridine derivative is obtained by performing a Hantzsch reaction of an azide compound with methyl aminocrotonate and 2-chloro-benzaldehyde, and the azido residue thereof is reduced. 
wherein Et and Me represent ethyl and methyl, respectively
However, this method gives a yield of only 19% and is not suitable for a large scale production due to the explosion hazard of the azide compound.
The method disclosed in Korean Patent Publication No. 86-1921 is illustrated as Scheme 2 below, wherein a Hantzsch reaction is conducted by using a derivative having a phthalimide amine protective group, followed by removing the amine protective group to give amlodipine. 
wherein Et and Me represent ethyl and methyl, respectively.
However, this method also has a problem in that the yield of Hantzsch reaction is rather low, e.g., 25%.
Korean Patent Publication No. 87-909 discloses a method for preparing amlodipine described as Scheme 3 below: a Hantzsch reaction is performed using a derivative whose amine group is protected by two benzyl groups, followed by removing the benzyl groups. 
wherein Bn, Et and Me represent benzyl, ethyl and methyl, respectively
This method also entails a low yield of 10%, and has the problem that two-step hydrogenation is required to remove the benzyl groups.
U.S. Pat. No. 5,389,654 describes a method of preparing amlodipine besylate (amlodipine benzenesulphonate) presented as Scheme 4 below, wherein a Hantzsch reaction is carried out using a derivative whose amino group is protected by a triphenylmethyl group, followed by removing the amine protective group by benzene sulfonic acid treatment. 
wherein Ph, Et and Me represent phenyl, ethyl and methyl, respectively
Again, this complicated method offers a very low yield of 7%.
According to the method disclosed in U.S. Pat. No. 6,046,337 which is represented as Scheme 5 below, a Hantzsch reaction is performed using a halogenated derivative and the halogen group of the resulting product is subsequently converted into an amine group. 
wherein Et and Me represent ethyl and methyl, respectively.
Since the chlorine-containing product is non-reactive in the subsequent amine substitution reation, it must be converted first to the corresponding iodine derivative. Accordingly, regardless of the halogen derivative used, the overall yield of amlodipine is 22% or below.
Accordingly, these prior art methods all suffer from the problem of low yield, calling for an improved method capable of producing amlodipine in a high yield.
Accordingly, it is a primary object of the present invention to provide an improved method of preparing amlodipine in a high yield.
In accordance with one aspect of the present invention, there is provided a method of preparing amlodipine of formula (I) which comprises:
(a) performing a Hantzsch reaction of a compound of formula (II) with aminocrotonate of formula (III) and 2-chlorobenzaldehyde of formula (IV) to obtain a compound of formula (V); and
(b) treating the compound of formula (V) with hydroxylamine hydrochloride in a mixture of water and an organic solvent: 
xe2x80x83wherein
R1 and R2 are independently halogen or C1-4 alkyl, or C1-4 alkyl substituted with hydrogen or alkoxy,
Me is methyl; and
Et is ethyl.
The method of the present invention may be represented as Scheme 6, as follows: 
wherein R1, R2, Et and Me are as defined above.
The pyrrole derivative of formula (II) is a novel compound, and in practicing the present invention, both R1 and R2 are preferably methyl. The pyrrole derivative of formula (II) may be prepared in a high yield in accordance with the method disclosed in [J. Chem. Soc., Perkin Trans. I, 2801, (1984)], which is presented herein as Scheme 7, wherein the amine residue is protected in the form of pyrrole. 
wherein R1, R2 and Et are as defined above.
The inventive method is particularly advantageous in that the pyrrole group makes it possible to carry out the substitution reaction even under a strong basic condition, in a high yield, i.e., 90%. Such a basic condition is not practicable when any of the conventional amine protecting groups is employed. Also, the pyrrole group can be easily converted into an amine by the action of hydroxylamine without affecting the adjacent ester-protecting group.
In step (a) of the inventive method, a high yield of a compound of formula (V) can be obtained by performing a Hantzsch reaction of a pyrrole derivative of formula (II) with methyl aminocrotonate of formula (III) and 2-chlorobenzaldehyde, the reaction being typically carried out by refluxing the pyrrole derivative, aminocrotonate and 2-chlorobenzaldehyde in 0.9-1.2:1:1 equivalent amounts in an organic solvent for twenty (20) hours. The organic solvent may be a C1-4 alkanol such as isopropanol and 1-butanol. The yield of this reaction is about 53% which is much higher than that of a conventional Hantzsch reaction.
In step (b), amlodipine can be obtained in a high yield by refluxing the compound of formula (V) in a mixture of water and an organic solvent for a period ranging from 4 to 5 hours in the presence of a hydroxylamine salt, preferably hydroxylamine hydrochloride, in an amount ranging from 15 to 25 equivalents, preferably 20 equivalents based on the amount of the compound of formula (V). A particularly high yield can be obtained when hydroxylamine hydrochloride is used in combination with triethylamine added in an amount of, e.g., 10 equivalents based on the amount of 1,4-dihydropyridine derivative. The organic solvent may be isopropanol, methanol, ethanol or 1-butanol, and it may be mixed with water in a volume ranging from 3 to 5, preferably 4 based on the volume of water.
In accordance with the present invention, the 1,4-dihydropyridine derivative of formula (V) can be obtained and converted into amlodipine in a much higher yield than was previously possible. This inventive method can thus be advantageously used in mass production of amlodipine.